The present invention relates to urea compounds which are useful for the treatment of acquired immunodeficiency syndrome (AIDS), their production and use.
HIV (human immunodeficiency virus) protease inhibitors have been developed for the treatment of AIDS and use of the protease inhibitors in combination with two conventional HIV reverse transcriptase inhibitors has provided further progress in the treatment of AIDS. However, these drugs and their combination use are not sufficient to eradicate AIDS, and new anti-AIDS drugs based on different activities and mechanisms are therefore required.
CD4 is a known receptor from which HIV invades a target cell. Recently, CCR5 has been discovered as a second receptor of macrophage-tropic HIV. CCR5 is a G-protein-coupled chemokine receptor having seven transmembrane domains. This chemokine receptor is thought to play an essential role in establishment and spread of HIV infection. In fact, it is reported that a person who is resistant to HIV infection in spite of several exposures retains mutation of homo deletion of CCR5 gene. Therefore, a CCR5 antagonist is expected to be a new anti-HIV drug.
As chemokine receptor antagonists, there are known aromatic urea derivatives (J. Biol. Chem., 1998, 273, 10095-10098), benzodiazepine derivatives (Japanese unexamined patent publication No. 9-249570), cyclam derivatives (Nat. Med., 1998, 4, 72-77), spiro piperidine derivatives (WO98/25604, 25605), acridine derivatives (WO98/30218), xanthene derivatives (WO98/04554), haloperidol derivatives (J. Biol. Chem., 1998, 273, 15687-15692., WO98/24325, 02151), benzazocine-type compound (Japanese unexamined patent publication No. 9-25572), benzimidazole derivatives (WO98/06703), piperazine and diazepine derivatives (WO97/44329), 3-di-substituted piperidine derivatives (Japanese unexamined patent publication No. 9-249566), 4-substituted piperidine derivatives (WO99/04794), substituted pyrrolidine derivatives (WO99/09984, WO99/38514), etc. However, so far, there has been no report that a CCR5 antagonist is developed as a therapeutic agent of AIDS.
In order to investigate an anti-AIDS drug having CCR5 antagonistic activity, it is necessary to clone CCR5 gene from human tissue derived cDNA library, to ligate said gene with a vector for expression in animal cells, to introduce said gene into animal cells and to obtain cells expressing CCR5. In addition, with using this transformant, it is necessary to screen a compound which strongly inhibits binding of CC chemokine RANTES, which is natural ligand, to CCR5. However, so far there has been no report on a low molecule compound having CCR5 antagonistic activity.
The present inventors diligently made extensive studies on compounds having CCR5 antagonistic activity and, as a result, they found that a compound represented by the formula (I) or a salt thereof exhibits superior CCR5 antagonistic activity and is useful for inhibition of HIV infection to human peripheral blood mononuclear cells (especially medicament for treatment or prevention of AIDS), and also that the compound has superior absorbability when orally administered. Based on the finding, the present invention was accomplished.
More specifically, the present invention relates to:
(1) a compound of the formula: 
[wherein R1 is a hydrocarbon group which may be substituted;
R2 is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
R3 is a halogen atom, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, an acyl group derived from a sulfonic acid, a C1-4 alkyl group which may be substituted, a C1-4 alkoxy group which may be substituted, an amino group which may be substituted, a nitro group or a cyano group;
R4 is a hydrogen atom or a hydroxy group;
n is an integer of 0 or 1;
p is an integer of 0 or 1 to 4];
or a salt thereof,
(2) the compound as shown in the above (1), wherein R3 is a halogen atom, a C1-4 alkyl group which may be substituted, a C1-4 alkoxy group which may be substituted, an amino group which may be substituted, a nitro group or a cyano group,
(3) the compound as shown in the above (1), wherein R1 is an alicyclic hydrocarbon group which may be substituted or an aryl group which may be substituted,
(4) the compound as shown in the above (1), wherein R1 is a hydrocarbon group which may be substituted by 1 to 4 substituent(s) selected from 1) a hydrocarbon group which may be substituted, 2) an heterocyclic group which may be substituted, 3) a C1-4 alkoxy group which may be substituted, 4) a C1-4 alkylthio group which may be substituted, 5) a C2-6 alkoxycarbonyl group which may be substituted, 6) a C1-6 alkanoyl group which may be substituted, 7) an amino group which may be substituted, 8) a cyclic amino group, 9) a halogen atom, 10) a nitro group, 11) a cyano group, 12) a carbamoyl group which may be substituted, 13) a sulfamoyl group which may be substituted and 14) an acyl group derived from a sulfonic acid,
(5) the compound as shown in the above (1), wherein R1 is a hydrocarbon group which may be substituted by 1 to 4 substituent(s) selected from 1) a hydrocarbon group which may be substituted, 2) a heterocyclic group which may be substituted, 3) a C1-4 alkoxy group which may be substituted, 4) a C1-4 alkylthio group which may be substituted, 5) a C2-6 alkoxycarbonyl group which may be substituted, 6) an amino group which may be substituted, 7) a halogen atom, B) a nitro group and 9) a cyano group,
(6) the compound as shown in the above (1), wherein R1 is a hydrocarbon group which may be substituted by 1 to 4 substituent(s) selected from 1) a hydrocarbon group which may be substituted, 2) a heterocyclic group which may be substituted, 3) a C1-4 alkylthio group which may be substituted, 4) a C2-6 alkoxycarbonyl group which may be substituted, 5) an amino group which may be substituted, 6) a halogen atom and 7) a nitro group,
(7) the compound as shown in the above (1), wherein R2 is an cyclic hydrocarbon group which may be substituted,
(8) the compound as shown in the above (1), wherein R3 is a halogen, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted or an acyl group derived from a sulfonic acid,
(9) the compound as shown in the above (1), wherein R3 is a halogen,
(10) the compound as shown in the above (1), wherein R4 is a hydrogen atom,
(11) the compound as shown in the above (1), wherein n is 0,
(12) the compound as shown in the above (1), wherein R1 is a hydrocarbon group selected from Group 3 which may be substituted by member(s) selected from Group 1; R2 is a cyclic hydrocarbon group selected from Group 10 which may be substituted by member(s) selected from Group 2, or a heterocyclic group selected from Group 4 which may be substituted by member(s) selected from Group 2; R3 is a halogen atom, a carbamoyl group, a N-mono-substituted carbamoyl group which is substituted by a member selected from Group 11, a N,N-di-substituted carbamoyl group which is substituted by a member selected from Group 11 and a member selected from Group 14, a cyclic aminocarbonyl group selected from Group 17, a sulfamoyl group, N-mono-substituted sulfamoyl group which is substituted by a member selected from Group 11, a N,N-di-substituted sulfamoyl group which is substituted by a member selected from Group 11 and a member selected from Group 14, a cyclic aminosulfonyl group selected from Group 20, an acyl group derived from a sulfonic acid selected from Group 15, a C1-4 alkyl group which may be substituted by member(s) selected from Group 2, a C1-4 alkoxy group which may be substituted by member(s) selected from Group 2, an amino group which may be substituted by member(s) selected from Group 8, a cyclic amino group selected from Group 9, a nitro group or a cyano group.
[In the above,
Group I includes
1) a hydrocarbon group which selected from Group 3 which may be substituted by member(s) selected from Group 2, 2) a heterocyclic group which selected from Group 4 which may be substituted by member(s) selected from Group 2, 3) a C1-4 alkoxy group which may be substituted by member(s) selected from Group 2, 4) a C1-4 alkylthio group which may be substituted by member(s) selected from Group 2, 5) a C2-6 alkoxycarbonyl group which may be substituted by member(s) selected from Group 2, 6) a C1-6 alkanoyl group, 7) an amino group which may be substituted by member(s) selected from Group 8, 8) a cyclic amino group selected from Group 9, 9) a halogen atom, 10) a nitro group, 11) a cyano group, 12) a carbamoyl group, 13) a mono-substituted carbamoyl group which is substituted by a member selected from Group 11, 14) di-substituted carbamoyl group which is substituted by a member selected from Group 11 and a member selected Group 14, 15) a cyclic amino carbamoyl group selected from Group 17, 16) a sulfamoyl group, 17) a N-mono substituted sulfamoyl group which is substituted by a member selected from Group 11, 18) a N,N-di-substituted sulfamoyl group which is substituted by a member selected from Group 11 and a member selected Group 14, 19) an acyl group derived from a sulfonic acid selected from Group 19,
Group 2 includes
1) a C1-6 alkoxy group, 2) a halogen atom, 3) a C1-6 alkyl group, 4) a C1-4 alkynyl group, 5) an amino group, 6) a hydroxy group, 7) a cyano group and 8) an amidino group,
Group 3 includes
1) a C1-6 alkyl group, 2) a C3-8 cycloalkyl group and 3) a C6-14 aryl group,
Group 4 includes
1) an aromatic monocyclic heterocyclic group selected from Group 5, 2) an aromatic condensed heterocyclic group selected from Group 6 and 3) a saturated or unsaturated non-aromatic heterocyclic group selected from Group 7,
Group 5 includes
furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl,
Group 6 includes benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenathrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and 1,2,4-triazolo[4,3-b]pyridazinyl,
Group 7 includes
oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl,
Group 8 includes
1) a C1-6 alkyl, 2) a C1-6 alkanoyl, 3) a C7-13 arylcarbonyl, 4) an optionally halogenated C2-6 alkoxycarbonyl, 5) a C1-6 alkylimidoyl, 6) a formylimidoyl and 7) an amidino,
Group 9 includes
1) 1-azetidinyl, 2) 1-pyrrolidinyl, 3) 1-piperidinyl, 4) 4-morpholinyl, 5) 1-piperazinyl and 6) 1-piperazinyl which may have a C1-6 alkyl, a C7-10 aralkyl and a C6-10 aryl at 4-position,
Group 10 includes
C3-9 cycloalkyl, 1-indanyl, 2-indanyl, C3-6 cycloalkenyl, C4-6 cycloalkanedienyl and C6-14 aryl,
Group 11 includes
1) a C1-6 alkyl group which may be substituted by member(s) selected from Group 12, 2) a C3-6 cycloalkyl group which may be substituted by member(s) selected from Group 12, 3) a C6-10 aryl group which may be substituted by member(s) selected from Group 12, 4) a C7-10 aralkyl group which may be substituted by member(s) selected from Group 12, 5) a C1-6 alkoxy group which may be substituted by member(s) selected from Group 12 and 6) a heterocyclic group selected from Group 13 which may be substituted by member(s) selected from Group 12,
Group 12 includes
1) a hydroxy group, 2) an amino group, 3) an amino group which is mono or di-substituted by member(s) selected from Group 16, 4) a halogen atom, 5) a nitro group, 6) a cyano group, 7) a C1-6 alkyl group which may be substituted by halogen atom(s) and 8) a C1-6 alkoxy group which may be substituted by halogen atom(s),
Group 13 includes
1) an aromatic heterocyclic group selected from Group 5 and Group 6 and 2) a saturated or unsaturated non-aromatic heterocyclic group selected from Group 7, each of which contains at least one heteroatom(s) selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom,
Group 14 includes
a C1-6 alkyl group, a C3-6 cycloalkyl group and a C7-10 aralkyl group,
Group 15 includes
1) a C1-10 alkylsulfonyl which may be substituted by member(s) selected from Group 12, 2) a C2-6 alkenylsulfonyl which may be substituted by member(s) selected from Group 12, 3) a C2-6 alkynylsulfonyl which may be substituted by member(s) selected from Group 12, 4) a C3-9 cycloalkylsulfonyl which may be substituted by member(s; selected from Group 12, 5) a C3-9 cycloalkenylsulfonyl which may be substituted by member(s) selected from Group 12, 6) a C6-14 arylsulfonyl which may be substituted by member(s) selected from Group 12 and 7) a C7-10 aralkylsulfonyl which may be substituted by member(s) selected from Group 12,
Group 16 includes
a C1-6 alkyl group, a C1-6 alkanoyl, a C7-13 arylcarbonyl and a C1-6 alkylsulfonyl,
Group 17 includes
1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 4-morpholinylcarbonyl and 1-piperazinylcarbonyl which may be substituted by member(s) selected from Group 18,
Group 18 includes
a C1-6 alkyl group, a C7-10 aralkyl group and a C6-10 aryl group,
Group 19 includes
a C1-10 alkylsulfonyl which may be substituted by member(s) selected from Group 12, a C2-6 alkenylsulfonyl which may be substituted by member(s) selected from Group 12, a C2-6 alkynylsulfonyl which may be substituted by member(s) selected from Group 12, a C3-9 cycloalkylsulfonyl which may be substituted by member(s) selected from Group 12, a C3-9 cycloalkenylsulfonyl which may be substituted by member(s) selected from Group 12, a C6-14 arylsulfonyl which may be substituted by member(s) selected from Group 12, and a C7-10 aralkylsulfonyl which nay be substituted by member(s) selected from Group 12, and
Group 20 includes
1-azetidinylsulfonyl, 1-pyrrolidinylsulfonyl, 1-piperidinylsulfonyl, 4-morpholinylsulfonyl and 1-piperazinylsulfonyl which may be substituted by member(s) selected from Group 18],
(13) the compound as shown in the above (1), wherein R1 is a C3-8 cycloalkyl group which may be substituted by member(s) selected from Group 1 ox a C6-14 aryl group which may be substituted by member(s) selected from Group 1,
(14) the compound as shown in the above (12), wherein R1 is 1) a C6-14 aryl group which may be substituted by a halogen atom, a C1-6 alkyl which may be substituted by halogen(s), a C1-4 alkylthio, a nitro, 3 carbamoyl, a sulfamoyl or a C1-6 alkylsulfonyl, 2) a C1-6 alkyl group which may be substituted by (i) a C2-6 alkoxycarbonyl group or (ii) a C1-6 alkyl group which may be substituted by phenyl(s) which may be substituted by C1-6 alkyl(s) or 3) a C3-8 cycloalkyl group which may be substituted by (i) a halogen atom, (ii) a C1-6 alkyl(s) which may be substituted by halogen(s) or (iii) a C1-6 alkoxy group which may be substituted by halogen(s);
R2 is a phenyl group which may be substituted by a halogen atom, a C3-6 alkyl, a C1-4 alkoxy or a cyano, a C3-8 cycloalkyl group or a pyridyl group;
R3 is (i) a halogen atom, (ii) a carbamoyl group, (iii) a sulfamoyl group which may have one or two C1-6 alkyl(s) or C3-6 cycloalkyl(s) at N-atoms, (iv) a cyclic aminosulfonyl group which is selected from Group 2D, (v) a C1-6 alkylsulfonyl group or (vi) C3-6 cycloalkylsulfonyl group;
R4 is a hydrogen atom;
n is 0 or 1 and
p is 0 or 1,
(15) the compound as shown in the above (12), wherein R1 is 1) a phenyl which may be substituted by a halogen atom, a C1-3 alkyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio or nitro, 2) a naphthyl, 3) a C1-6 alkyl group which may be substituted by (i) a C2-3 alkoxycarbonyl, (ii) phenyl or (iii) 3-isopropenylphenyl, or 4) cyclohexyl;
R2 is a phenyl group which may be substituted by a halogen atom, methyl, methoxy or cyano, a cyclohexyl group or a 3-pyridyl group;
R3 is (i) a halogen atom, (ii) a carbamoyl group, (iii) a 4-morpholinylsulfonyl group or (iv) a methylsulfonyl group,
R4 is a hydrogen atom;
n is 0 or 1; and
p is 0 or 1,
(16) the compound as shown in the above (12), wherein R1 is a phenyl group which may be substituted by a halogen atom or a C1-3 alkyl; R2 is a phenyl group which may be substituted by a halogen atom and methyl(s);
R3 is (i) a halogen atom, (ii) a carbamoyl group, (iii) a sulfamoyl group which may be substituted by oe or two members selected from the group consisting of C1-6 alkyl and C3-6 cycloalkyl at N-atoms, (iv) a cyclic aminosulfonyl group selected from Group 20, (v) a C1-6 alkylsulfonyl group or (vi) a C3-6 cycloalkyl sulfonyl group;
R4 is a hydrogen atom;
n is 0; and
p is 0 or 1,
(17) the compound as shown in the above (1), which is N-[3-(4-benzyl-1-piperidinyl)propyl]-Nxe2x80x2-(4-chlorophenyl)-N-phenylurea, Nxe2x80x2-(4-chlorophenyl)-N-{3-[4-(4-fluorobenzyl)-1-piperidinyl]propyl}-N-phenylurea, Nxe2x80x2-(4-chlorophenyl)-N-(3-{4-[4-(4-morpholinylsulfonyl)benzyl]-1-piperidinyl)propyl}-N-phenylurea, Nxe2x80x2-(4-chlorophenyl)-N-(3-{4-[4-(4-methylsulfonyl)benzyl]-1-piperidinyl}propyl)-N-phenylurea, 4-{[1-(3-{[(4-chloroanilino)carbonyl]anilino}propyl)-4-piperidinyl]methyl}benzamide,
or a salt thereof,
(18) a prodrug of the compound of the formula (I) or a salt thereof,
(19) a pharmaceutical composition containing a compound of the formula (I), a salt thereof or a prodrug thereof,
(20) the pharmaceutical composition as shown in the above (19), which is a chemokine receptor antagonist,
(21) the pharmaceutical composition as shown in the above (19), which is a CCR5 antagonist,
(22) the composition as shown in the above (19), which is for the treatment or prevention of infectious disease of HIV,
(23) the composition as shown in the above (19), which is for the treatment or prevention of AIDS,
(24) the composition as shown in the above (19), which is for the prevention of the progression of AIDS,
(25) the composition as shown in the above (22), further comprises a protease inhibitor and/or a reverse transcriptase inhibitor,
(26) the composition a1s shown in the above (25), wherein the reverse transcriptase inhibitor is zidovudine, didanosine, zalcitabine, lamivudine, stavudine, abacavir, nevirapine, delavirdine or efavirenz,
(27) the composition as shown in the above (25), wherein the protease inhibitor is saquinavir, ritonavir, indinavir, amprenavir or nelfinavir,
(28) use of a compound of the formula (I), a salt thereof or prodrug thereof for the manufacture of an antagonist of a chemokine receptor,
(29) use of a compound of the formula (I), a salt thereof or prodrug thereof for the manufacture of a CCR5 antagonist,
(30) use of a compound of the formula (I), a salt thereof or prodrug thereof, for the manufacture of a medicament for the treatment or prevention of infectious disease of HIV,
(31) use of a compound of the formula (I), a salt thereof or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of infectious disease of HIV which is used in combination with a protease inhibitor and/or a reverse transcriptase inhibitor,
(32) a method for antagonizing CCR5 which comprises administering to a mammal in need thereof an effective amount of the compound of the formula (I), a salt thereof or a prodrug thereof,
(33) a method for producing a compound of the formula (I) or a salt thereof, which comprises reacting a compound of the formula: 
xe2x80x83wherein each symbol has the meaning given above, or a salt thereof, with a compound of the formula:
R1xe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83(III)
xe2x80x83wherein R1 has the meaning given above, or a salt thereof,
(34) a method for producing a compound of the formula (I) or salt thereof, which comprises reacting a compound of the formula: 
xe2x80x83wherein X is a leaving group, and other symbols have the meanings given above or a salt thereof, with a compound of the formula: 
xe2x80x83wherein each symbols has the same meaning given above, or a salt thereof in the presence of base.
Examples of the hydrocarbon group in the xe2x80x9ca hydrocarbon group which may be substitutedxe2x80x9d represented by R1 include, for example, an aliphatic hydrocarbon group, an alicyclic hydrocarbon group and an aryl group etc. Examples of the aliphatic hydrocarbon group include a C1-6 alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl etc. Examples of the xe2x80x9calicyclic hydrocarbon groupxe2x80x9d include a C3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Examples of the aryl group include a C6-14 aryl group such as phenyl, naphthyl (1-naphthyl, 2-naphthyl), etc, are preferred.
Examples of the substituent(s) in the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d represented by R1 include a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a C1-4 alkoxy group which may be substituted, a C1-4 alkylthio group which may be substituted, a C2-6 alkoxycarbonyl group which may be substituted, a C1-6 alkanoyl group which may be substituted, an amino group which may be substituted, a nitro group, a cyano group, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, an acyl group derived from a sulfonic acid, etc.
Examples of the hydrocarbon group(s) in the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d are those similar to the xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d, which is represented by R1. Among these substituents, a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-14 aryl group are preferred. These examples may include the substituents as mentioned above for R1. Examples of the substituents in the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d include, for example, a lower alkoxy group (e.g., a C1-6 alkoxy group such as methoxy, ethoxy, propoxy, etc.), a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, propyl, etc.), a lower alkenyl group (e.g., a C1-4 alkenyl group such as vinyl, 1-propenyl, 2-propenyl, isopropenyl, buternyl, isobutenyl, etc.), an amino group, a hydroxy group, a cyano group, an anidino group etc. The hydrocarbon in xe2x80x9chydrocarbon which may be substitutedxe2x80x9d may have 1 to 3 substituent(s) as described above at any possible position.
Examples of the heterocyclic group in the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d (the substituent in the xe2x80x9chydrocarbon group which may be substituted by R1xe2x80x9d) include, for example, an aromatic heterocyclic group, saturated or unsaturated non-aromatic heterocyclic group (alicyclic heterocyclic group) etc., which contains, besides carbon atoms, at least one heteroatom(s) (preferably 1 to 4 heteroatom(s), more preferably, 1 to 2 heteroatom(s)) consisting of 1 to 3 kind(s) of heteroatom""s) (preferably 1 to 2 kinds of heteroatom(s)) selected from an oxygen atom, a sulfur atom, a nitrogen atom, etc.
Examples of the xe2x80x9caromatic heterocyclic groupxe2x80x9d include an aromatic monocyclic heterocyclic group such as a 5 or 6-membered aromatic monoyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.); an aromatic fused heterocyclic group such as a 8 to 12-membered aromatic fused heterocyclic group (e.g., benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisooxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridaizinyl, etc.); etc., preferably, a heterocyclic group consisting of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group fused with a benzene ring or heterocyclic group consisting of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group fused with the same or different above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group, etc.
Examples of the xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d include a 3 to 8-membered (preferably 5 or 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) such as oxiranyl, azetidinyl, oxetanyl, thiethanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.
Examples of the xe2x80x9csubstituent(s)xe2x80x9d of the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d (substituent(s) of the hydrocarbon group which may be substituted, which is represented by R1) are those similar to the xe2x80x9csubstituent(s)xe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d that is(are) the xe2x80x9csubstituent(s)xe2x80x9d of the hydrocarbon group which may be substituted, which is represented by R1.
Examples of xe2x80x9cC1-4 alkoxy groupxe2x80x9d in the xe2x80x9cC1-4 alkoxy group which may be substitutedxe2x80x9d include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc. Example of xe2x80x9cC1-4 an alkylthio groupxe2x80x9d in the xe2x80x9cC1-4 an alkylthio group which may be substitutedxe2x80x9d include, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, etc. Example of the xe2x80x9cC2-6 alkoxycarbonyl groupxe2x80x9d in xe2x80x9cC2-6 alkoxycarbonyl group which may be substitutedxe2x80x9d include, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, etc.
Examples of the xe2x80x9cC1-6 alkanoyl groupxe2x80x9d in the xe2x80x9cC1-6 alkanoyl group which may be substitutedxe2x80x9d include, for example, formyl, acetyl, propionyl, pivaloyl etc. Examples of the substituent in the xe2x80x9cC1-4 alkoxy group which may be substitutedxe2x80x9d, xe2x80x9cC1-4 alkylthio group which may be substitutedxe2x80x9d, and xe2x80x9cC1-6 alkoxycarbonyl group which may be substitutedxe2x80x9d, xe2x80x9cC1-6 alkanoyl group which may be substitutedxe2x80x9d are those similar to the substituent(s) of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d, which are the substituent(s) of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d represented by R1.
Examples of the substituent(s) of the xe2x80x9camino group which may be substitutedxe2x80x9d include, for example, a lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group derived from a carboxylic acid (e.g., a C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc.), a C7-15 arylcarbonyl such as benzoyl, etc., an acyl group derived from a sulfonic acid (e.g., a C1-6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.), an optionally halogenated C2-6 alkoxycarbonyl (e.g., trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), etc. In addition, the xe2x80x9camino groupxe2x80x9d in the xe2x80x9camino group which may be substitutedxe2x80x9d may be substituted with an imidoyl group which may be substituted (e.g., a C1-6 alkylimidoyl, formylimidoyl, amidino, etc.), etc. Alternatively, two substituents of the amino group may form a cyclic amino group together with a nitrogen atom. Examples of said cyclic amino group include e.g. 3 to 8-membered (preferably 5 or 6-membered) cyclic amino group such as 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl and 1-piperazinyl which may have at the 4-position a lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), an aralkyl group (e.g. a C7-10 aralkyl group such as benzyl, phenethyl, etc.), an aryl group (e.g. a C6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc.), etc.
Examples of the xe2x80x9ccarbamoyl group which may be substitutedxe2x80x9d include unsubstituted carbamoyl, a N-mono-substituted carbamoyl group and a N,N-di-substituted carbamoyl group.
The xe2x80x9cN-mono-substituted carbamoyl groupxe2x80x9d is a carbamoyl group having one substituent on the nitrogen atom and the substituent include, for example, a lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), a cycloalkyl group (e.g., a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), an aryl group (e.g., a C6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc.), an aralkyl group (e.g., a C7-10 aralkyl group, preferably a phenyl-C1-4 alkyl group such as benzyl, phenethyl, etc.), a heterocyclic group (e g., the above described xe2x80x9cheterocyclic groupxe2x80x9d as the substituent of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d represented by R1, etc.), etc. The lower alkyl group, the cycloalkyl group, the aryl group, the aralkyl group and the heterocyclic croup as described above may have substituent(s), and the substituent(s) include, for example, a hydroxy group, an amino group which may be substituted [the amino group may have 1 or 2 substituent(s) (e.g. a lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group (e.g., a C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc., an arylcarbonyl such as benzoyl, etc., a C1-6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.), etc.)], a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a lower alkyl group which may be substituted with 1 to 5 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine, etc.), a lower alkoxy group which may be substituted with 1 to 5 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine, etc.), etc. The lower alkyl group) includes, e.g. a C1-6 alkyl group such as methyl, ethyl, n-prop)yl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. and in particular methyl, ethyl, etc. are preferable. Said lower alkoxy group include e.g. a C1-6 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. and in particular methoxy, ethoxy, etc. are preferable. The above described lower alkyl group, cycloalkyl group, aryl group, aralkyl group and heterocyclic group may have 1, 2 or 3 (preferably 1 or 2) substituent(s).
The xe2x80x9cN,N-di-substituted carbamoyl groupxe2x80x9d is a carbomoyl group having two substituents on the nitrogen atom. Examples of one of the substituents include the same as those of the above described xe2x80x9cN-mono-substituted carbamoly groupxe2x80x9d and examples of the other substituent include e.g. a lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), a C3-6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), a C7-10 aralkyl group (e.g., benxyl, phenethyl, etc., preferably phenyl-C1-4 alkyl group, etc.), etc. In addition, two substituents of the xe2x80x9cN,N-di-substituted carbamoyl groupxe2x80x9d may form a cyclic aminocarbonyl group together with a nitrogen atom. Examples of said cyclic aminocarbonyl group include, e.g., 3 to 8-membered (preferably 5 or 6-membered) cyclic aminocarbonyl group such as 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 4-morpholinylcarbonyl, 1-piperazinylcarbonyl and 1-piperazinylcarbonyl which may have a lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), an aralkyl group (e.g., a C7-10 aralkyl group such as benzyl, phenethyl, etc.), an aryl group (e.g., a C6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc.), etc. at the 4-position.
Examples of the xe2x80x9csulfamoyl group which may be substitutedxe2x80x9d include an unsubstituted sulfamoyl group, a N-mono-substituted sulfamoyl group and a N,N-di-substituted sulfamoyl group.
The xe2x80x9cN-mono-substituted sulfamoyl groupxe2x80x9d is a sulfamoyl group having one substituent at the nitrogen atom, and examples of the substituent include those mentioned for the substituents of N-mono-substituted carbamoyl group.
The xe2x80x9cN,N-di-substituted sulfamoyl groupxe2x80x9d is a sulfamoyl group having two substituents at the nitrogen atom, and examples of the substituents include those mentioned as the substituents of the N,N-di-substituted carbamoyl group.
Examples of the xe2x80x9cacyl group derived from a sulfonic acidxe2x80x9d include a sulfonyl group substituted by a hydrocarbon group, and preferably, include an acyl group such as C1-10 alkylsulfonyl, C2-6 alkenylsulfonyl, C2-6 alkynylsulfonyl, C3-9 cycloalkylsulfonyl, C3-9 cycloalkenylsulfonyl, C6-14 arylsulfonyl, C7-10 aralkylsulfonyl. Examples of the C1-10 alkyl include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, etc. Examples of the C2-6 alkenyl include, for (example, vinyl, allyl, 1-propenyl, isopropenyl, 2-butenyl, 3-butenyl, 2-hexenyl, etc. Examples of C2-6 alkynyl include, for example, ethynyl, 2-propynyl, 2-butynyl, 5-hexynyl, etc. Examples of the C3-9 cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, etc. Examples of the C3-9 cycloalkenyl include, for example, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 3-cyclohexen-1-yl, 3-cycloocten-1-yl, etc. Examples of the C6-14 aryl include, for example, phenyl, 1-naphthyl, 2-naphthyl, etc. Examples of the C7-10 aralkylsulfonyl include, for example, benzyl, phenethyl, etc. These hydrocarbon groups which are the substituents of the sulfonyl may be substituted. Examples of these substituents include, for example, hydroxy group, amino group which may be substituted [(the amino group may be substituted by one or two C1-6 alkyl(s) (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group (e.g., C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc., aryl carbonyl such as benzoyl, etc., C1-6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.)), halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, lower alkyl which may be substituted by 1 to 5 halogen atom(s) (e.g. fluorine, chlorine, bromine, iodine, etc.), C1-6 alkoxy which may be substituted by 1 to 5 halogen atom(s) (e.g. fluorine, chlorine, bromine, iodine, etc.). Examples of the lower alkyl group include, for example, C1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., and preferably include methyl, ethyl, etc. The lower alkoxy group includes, for example, C1-6 alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc, and preferably include methoxy, ethoxy, etc. Preferably, one, two or three (preferably one or two) from these substituents is(are) used, wherein the substituents may be the same or different.
xe2x80x9cCyclic hydrocarbon groupxe2x80x9d in the xe2x80x9ccyclic hydrocarbon group which may be substitutedxe2x80x9d of R2 include alicyclic hydrocarbon group and aryl group.
Examples of the xe2x80x9calicyclic hydrocarbon groupxe2x80x9d include, for example, a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, a cycloalkanedienyl group, etc. Examples of the xe2x80x9ccycloalkyl groupxe2x80x9d include, for example, a C3-9 cycloalkyl (preferably, a C3-8 cycloalkyl) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc., and a fused ring suhc as 1-indanyl, 2-indanyl, etc. Examples of the xe2x80x9ccycloalkenyl groupxe2x80x9d include , for example, a C3-6 cycloalkenyl group such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, etc. Examples of the xe2x80x9ccycloalkanedienyl groupxe2x80x9d include, for example, a C4-6 cycloalkanedienyl group such as 2,4-cyclopentanedien-1-yl, 2,4-cyclohexanedien-1-yl, 2,5-cyclohexanedien-1-yl, etc. In particular, a C3-8 cycloalkyl is preferable.
Examples of the xe2x80x9caryl groupxe2x80x9d exemplified by the hydrocarbon group include, for example, a monocyclic or fused aromatic hydrocarbon group. Among others, a C6-14 aryl group such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, 4-indanyl, 5-indanyl, etc. are preferable. In particular, phenyl, 1-naphthyl, 2-naphthyl, etc. are preferable.
Examples of the xe2x80x9csubstituent(s)xe2x80x9d in the xe2x80x9ccyclic hydrocarbon group which may be substitutedxe2x80x9d represented by R2 are those similar to the xe2x80x9csubstituentxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d described as the substituent(s) of the hydrocarbon group which may be substituted, which are represented by R1.
Examples of the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d of R2 are those similar to the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d described as the substituent(s) of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d, which are represented by R1.
The halogen atom represented by R3 include, for example, fluorine, chlorine, bromine, iodine, etc.
The xe2x80x9ccarbomoyl group which may be substitutedxe2x80x9d, xe2x80x9csulfamoyl group which may be substitutedxe2x80x9d and xe2x80x9cacyl group derived from a sulfonic acidxe2x80x9d represented by R3 are those similar to the xe2x80x9ccarbamoyl group which may be substitutedxe2x80x9d, xe2x80x9csulfamoyl group which may be substitutedxe2x80x9d and xe2x80x9cacyl group derived from a sulfonic acidxe2x80x9d, which are represented by R1.
Examples of the xe2x80x9cC1-4 alkyl groupxe2x80x9d of the xe2x80x9cC1-4 alkyl group which may be substitutedxe2x80x9d represented by R3 include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl. Examples of the xe2x80x9cC1-4 alkoxy groupxe2x80x9d of the xe2x80x9cC1-4 alkoxy group which may be substitutedxe2x80x9d represented R3 include, for example, methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, tert-butoxy.
Example of the substituent(s) in the xe2x80x9cC1-4 alkyl group which may be substitutedxe2x80x9d and xe2x80x9cC1-4 alkoxy group which may be substitutedxe2x80x9d, which is represented by R3 are those similar to the xe2x80x9csubstituent(s)xe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d that is(are) the xe2x80x9csubstituent(s)xe2x80x9d of xe2x80x9cthe hydrocarbon group which may be substitutedxe2x80x9d, which is represented by R1.
Examples of the substituents of xe2x80x9camino group which may be substitutedxe2x80x9d represented by R3 include, for example, lower alkyl group (e.g., C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group derived from carboxylic acid (e.g., C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc.), for example, C7-15 arylcarbonyl such as benzoyl, etc, an acyl group derived from sulfonic acid (e.g., C1-6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.), an optionally halogenated C1-6 alkoxy-carbonyl (e.g., trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), etc. In addition, the xe2x80x9camino groupxe2x80x9d of the xe2x80x9camino group which may be substitutedxe2x80x9d may be substituted with an imidoyl group which may be substituted (e.g., a C1-6 alkylimidoyl, formylimidoyl, amidino, etc.), etc. and two substituents of the xe2x80x9camino groupxe2x80x9d may form a cyclic amino group together with a nitrogen atom. Examples of said cyclic amino group include, for example, 3 to 8-membered (preferably, 5 or 6-membered) cyclic amino group such as 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl and 1-piperazinyl which may have a lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), an aralkyl group (e.g., a C7-10 aralkyl group such as benzyl, phenethyl, etc.), an aryl group (e.g., a C6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc.), etc. at the 4-position.
Examples of the leaving group represented by X include, for example, a halogen atom (e.g., a chlorine atom, a bromine atom, an iodine atom, etc.), an alkyl or aryl sulfonyloxy group (e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.), etc.
Examples of the salt of a compound of the formula (I) of the present invention include a salt with an acid, for example, a salt with inorganic acid (e.g., hydrochloric acid salt, sulfuric acid salt, hydrobromic acid salt, phosphoric acid salt, etc.), a salt of an organic acid (e.g., acetic acid salt, trifluoroacetic acid salt, succinic acid salt, maleic acid salt, fumaric acid salt, propionic acid salt, citric acid salt, tartaric acid salt, lactic acid salt, oxalic acid salt, methanesulfonic acid salt, p-toluenesulfonic acid salt, etc.), etc., a salt with a base (e.g., an alkali metal salt such as potassium salt, sodium salt, lithium salt, etc., an alkaline earth metal salt such as calcium salt, magnesium salt, etc., ammonium salt, a salt with an organic base such as trimethylamine salt, triethylamine salt, tert-butyl dimethyl amine salt, dibenzyl methylamine salt, benzyl dimethylamine salt, N,N-dimethylaniline salt, pyridine salt, quinoline salt, etc.).
The compound of the formula (I) or salt thereof may also be hydrated. Hereinafter the compound of the formula (I), its salt and its hydrate are referred to as Compound (I).
A prodrug of the Compound (I) of the present invention means a compound which is converted to the Compound (I) having inhibitory activity of CCR5 by a reaction due to an enzyme, an gastric acid, etc. in vivo.
Examples of the prodrug of the Compound (I) include a compound wherein an amino group of the Compound (I) is substituted with acyl, alkyl, phosphoric acid (e.g. a compound wherein an amino group of the Compound (I) is substituted with eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, acetoxymethyl, tert-butyl, etc.); a compound wherein a hydroxy group of the Compound (I) is substituted with an acyl, an alkyl, a phosphoric acid group, a boric acid group (e.g. a compound wherein a hydroxy group of the Compound (I) is substituted with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl, etc.); a compound wherein a carboxyl group of the Compound (I) is modified to ester, amide (e.g. a compound wherein a carboxyl group of the Compound (I) is modified to ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester, cyclohexyloxycarbonylethyl ester, methyl amide, etc.); etc. These prodrugs can be produced by per se known method.
The prodrug of the Compound (I) may be a compound which is converted into the Compound (I) under the physiological conditions as described in xe2x80x9cPharmaceutical Research and Developmentxe2x80x9d, Vol. 7 (Drug Design), pages 163-198 published in 1990 by Hirokawa Publishing Co. (Tokyo, Japan).
The prodrug of the Compound (I) may be distinct entity or in the form of a pharmaceutically acceptable salts. Examples of said salt include a salt with an inorganic base (e.g., an alkaline metal such as sodium, potassium, etc.; an alkaline earth metal such as (calcium, magnesium, etc.; transition metal such as zinc, iron, copper, etc.); an organic base (e.g., an organic amine such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, etc.; a basic amino acid such as arginine, lysine, ornithine, etc.); etc., when the prodrug of the Compound (I) has an acidic group such as a carboxyl group, etc.
Examples of said salt also include a salt with an inorganic acid or an organic acid (e.g., hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.); an acidic amino acid such as aspartic acid, glutamic acid, etc.; etc., when the prodrug of the Compound (I) has a basic group such as an amino group, etc.
The prodrug of the Compound (I) may be hydrated or unhydrated.
The Compound (I) may have one or more asymmetric carbon(s) in the molecule. The compound of the present invention may have both R-configuration and S-configuration as to the asymmetric carbon(s).
Unless otherwise mentioned, the xe2x80x9clowerxe2x80x9d in xe2x80x9ca lower alkyl groupxe2x80x9d, xe2x80x9ca lower alkoxy groupxe2x80x9d, etc., throughout the present specification means a straight, branched or cyclic carbon chain having 1 to 6 carbon(s).
Among the compounds represented by the formulas (II) to (VI), the compound having a basic group or acidic group may form an acid addition salt or a salt with a base, respectively. Examples of the salt include those mentioned as the salt of the compound represented by the formula (I). Hereinafter the compounds represented by each formula and a salt thereof are referred to as Compound (symbol of the formula). For example, the compound represented by the formula (II) and salt thereof are simply referred to as Compound (II).
Compound (I) can, for example, be prepared by the following methods:
Production 1
As shown in the following formula, Compound (II) can be reacted with Compound (III) to give Compound (I). 
(In the above formulas, each symbol has the same meaning as defined above.)
The reaction is usually carried out in a solvent inert to the reaction. Examples of the solvent include an ether (e.g., ethyl ether, diisopropyl ether, dimethoxy ethane, tetrahydrofuran, dioxane, etc.), a halogenated hydrocarbon (e.g., dichloromethane, dicholoroethane, chloroform, etc.), an aromatic solvent (e.g., toluene, chlorobenzene, xylene, etc.), acetonitrile, N,N-dimethylformamide (DMF), acetone, methylethyl ketone, dimethylsulfoxide (DMSO), water, etc., or a mixed solvent thereof. Among them, acetonitrile, dichloromethane, chloroform, etc. are preferable. The reaction is usually carried out by using 1 to 5 equivalents), preferably 1 to 3 equivalents of Compound (III) relative to 1 equivalent of Compound (II). The reaction temperature ranges from xe2x88x9220xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to room temperature, and reaction time is usually 5 minutes to 100 hours. The reaction may smoothly proceed by using a base. As the base, an inorganic base and an organic base can be used effectively. Examples of the inorganic base include a hydroxide, a hydride, a carbonate, a bicarbonate of alkaline metal or alkaline earth metal. Among them, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate are preferable. Examples of the organic base preferably include a tertiary amine such as triethylamine.
Compound (II) can be produced, for example, by a method described in Synthetic Comm., 1991, 20, 3167-3180. That is, the above compound can be produced by the following method by applying an addition reaction of amines or amides to unsaturated bond. 
In the above formula, each symbol has the same meaning as defined above.
The compound can be produced by reacting acrolein (VI) with Compound (V), followed by reacting the resulting compound with Compound (VIII) under a condition of reduction. The reaction of Compound (VI) with Compound (V) is usually carried out in a solvent inert to the reaction in the presence of a base. Examples of the base include 1) a strong base such as hydride of alkali metal or alkaline earth metal (e.g., lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), an amide of an alkali metal or an alkaline earth metal (e.g., lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc.), a lower alkoxide of alkali metal or alkaline earth metal (e.g., sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), etc., 2) an inorganic base such as a hydroxide of an alkali metal or an alkaline earth metal (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), a carbonate of an alkali metal or an alkaline earth metal (e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.), a bicarbonate of alkali metal or alkaline earth metal (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), etc., 3) an organic base, etc., such an amine as triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo[5.4.0]-7-undecene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), etc., and such basic heterocyclic Compound, etc., as pyridine, imidazole, 2,6-lutidine, etc. Examples of the solvent include those mentioned in the reaction of Compound (II) with Compound (III). These solvents can be used solely or in combination. Compound (VII) can be obtained in the reaction.
Examples of the reducing agent for the reaction of Compound (VII) with Compound (VIII) include sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc. The used amount of the reducing agent is usually in the range of 1 to 10 equivalents, preferably in the range of 1 to 4 equivalents relative to 1 equivalent of Compound (VII). The reaction temperature ranges xe2x88x9220 to 50xc2x0 C., preferably 0xc2x0 C. to room temperature, and reaction time is 0.5 to 24 hours.
Catalytic reduction reaction is carried out in the presence of a catalytic amount of a metal catalyst such as Raney nickel, platinum oxide, metallic palladium, palladium-carbon, etc., in an inert solvent (e.g., an alcohol such as methanol, ethanol, isopropanol, t-butanol, etc.), at room temperature to 100xc2x0 C., under a hydrogen pressure of 1 to 100 atm for 1 to 48 hours.
Production 2
Compound (I) can be produced by reacting Compound (IV) with Compound (V) as shown below. 
(In the above formulas, each symbol has the same meaning as defined above.)
The reaction can be carried out by a manner similar to that described in Organic Functional Group Preparations 2nd ed., (Academic Press, Inc.).
The reaction is usually carried out in a solvent inert to the reaction. Examples of the solvent include an alcohol, an ether, a halogen solvent, an aromatic solvent, acetonitrile, N,N-dimethylformamide (DMF), acetone, methylethyl ketone, dimethylsulfoxide (DMSO), etc. These solvents can be used solely or in combination. Among them, acetonitrile, dimethylformamide, acetone, ethanol, etc., are preferable. The reaction temperature ranges usually from room temperature to 100xc2x0 C., preferably from room temperature to 50xc2x0 C., and the reaction time is usually 0.5 to 1 day. In this reaction, a base is usually added in an amount of 1 to 3 equivalents relative to 1 equivalent of Compound (IV), but it is not essential. Examples of the base include those mentioned in the reaction of Compound (II) with Compound (III).
Compound (IV) used as a starting material in the reaction can be produced from Compound (III) by a known conventional method.
Production 3
Compound (I) can be produced by reacting a compound of the formula (IX) with a compound of the formula (V) under a reduction condition as shown below. 
(In the above formulas, each symbol has the same meaning as defined above.)
The reaction is carried out by reacting Compound (IX) with Compound (V) in an appropriate solvent (e.g., water, an alcohol, an ether, a halogenated solvent, acetonitrile, or a mixed solvent of two or more of these solvents, etc.), if necessary, by the addition of acidic substance such as acetic acid, trifluoroacetic acid, etc., in the presence of 1 to 5 equivalents, preferably 1 to 1.5 equivalent of a reducing agent. The reducing agent and the reaction condition mentioned in Production 1 can be applied for this reaction.
Compound (IX) used as a starting material in the reaction can be produced from Compound (III) by a known conventional method.
The Compound (I) of the present invention has potent CCR antagonistic activity (in particular, potent CCR5 antagonistic activity) and therefore can be used for the treatment or prevention of various infectious diseases of HIV in human, for example, AIDS. The compound (I) of the present invention is low toxic and safely used.
The Compound (I) of the present invention can be used as a CCR5 antagonist, for example, a drug for treatment or prevention of AIDS or a drug for the prevention of the progression of AIDS.
The compound of the present invention can be formulated by mixing individually or simultaneously with pharmaceutically acceptable carriers, excipients, binders, diluents or the like, which can be administered orally or non-orally as a pharmaceutical composition. It is well absorbed by orally. It can be administrated as tablets, capsules, granules and powders.
The dose per day of the compound (I) varies depending on the condition and body weight of a patient, administration route, etc. Typical daily dose per adult patient (body weight: 50 Kg) for oral administration is about 5 to 1000 mg, preferably about 10 to 600 mg, more preferably about 10 to 300 mg, and in particular about 15 to 150 mg, as an active ingredient [the compound (I)] and the compound (I) is administered once or 2 to 3 times per day.
The compound (I) of the present invention may be used in combination with other drugs for the treatment or prevention of infectious disease of HIV (in particular, a drug for the treatment or prevention of AIDS). In this case, these drugs can be formulated by mixing individually or simultaneously with pharmaceutically acceptable carriers, excipients, binders, diluents or the like, which can be administered orally or non-orally as a pharmaceutical composition for the treatment or prevention of infectious disease of HIV. In the case of formulating these effective components individually, while the individually formulated agents can be administered in the form of their mixture prepared by using e.g. a diluent when administered, the individually formulated agents can also be administered separately or simultaneously or with time intervals to the one and same subject. A kit for administering the individually formulated effective components in the form of their mixture prepared by using e.g. a diluent when administered (e.g. a kit for injection which comprises two or more ampoules each comprising a powdery component and a diluent for mixing and dissolving two or more components when administered, etc.), a kit for administering the individually formulated agents simultaneously or with time intervals to the one and the same subject (e.g. a kit for tablets to be administered simultaneously or with time intervals, characterized by having two or more tablets each comprising an agent and said tablets being put in one or separate bags and, if necessary, a column to describe time to be administered each agent, etc.), etc. are also included by the pharmaceutical composition of the present invention.
Example of the other pharmaceutical agent for the treatment or prevention of infectious disease of HIV to be used in combination with the compound (I) of the present invention include nucleoside reverse transcriptase inhibitor such as zidovudine, didanosine, zalcitabine, lamivudine, stavudine, abacavir, adefovir, adefovir dipivoxil, fozivudine tidoxil, etc.; non-nucleoside reverse transcriptase inhibitor (including an agent having anti-oxidative activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, etc.; protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, palinavir, lasinavir, etc.; etc.
As the nucleoside reverse transcriptase inhibitor, zidovudine, didanosine, zalcitabine, lamivudine, stavudine, etc. are preferable; as the non-nucleoside reverse transcriptase inhibitor, nevirapine, delavirdine, etc. are preferable; and as the protease inhibitor, saquinavir, ritonavir, indinavir, nelfinavir, etc. are preferable.
The compound (I) of the present invention may be used in combination with, for example, CXCR4 antagonist (CXCR4 being a second receptor of T cell-tropic HIV-1) such as AMD-3100, etc., an antibody against HIV-1 surface antigen, HIV-1 vaccine, etc., in addition to the above-mentioned protease inhibitor, reverse transcriptase inhibitor, etc.
When the compound (I) is used in combination with a reverse transcriptase inhibitor and/or a protease inhibitor, the dose of the reverse transcriptase inhibitor or the protease inhibitor ranges, for example, from about 1/200 to 1/2 or more of usual dose to about 2 to 3 times or less of usual dose. In case that two or more drugs are used in combination, each dose of the drugs is appropriately adjusted if one drug affects metabolism of the other drug, while each dose of the drugs when they are used in combination is generally the same as the dose when they are used alone.
Typical daily dose of the reverse transcriptase inhibitor and the protease inhibitor is as follows:
In case of combination use of the compound (I) with a reverse transcriptase inhibitor and/or a protease inhibitor preferred embodiments are shown below.
(i) A drug containing about 10 to 300 mg of the compound (I) and a drug containing about 50 to 200 mg of zidovudine to one adult patient (body weight: 50 Kg) are administered. Each of the drugs may be administered to the one and the same subject simultaneously or with time intervals of 12 hours or less.
(ii) A drug containing about 10 to 300 mg of the compound (I) and a drug containing about 300 to 1200 mg of saquinavir to one adult patient (body weight: 50 Kg) are administered. Each of the drugs may be administered to the one and the same subject simultaneously or with time intervals of 12 hours or less.